Therapie des Multiplen Myeloms Alles im Fluss? Peter Neumeister, MD Division Hematology Medical University Graz

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1 Therapie des Multiplen Myeloms Alles im Fluss? Peter Neumeister, MD Division Hematology Medical University Graz

2 Newly Diagnosed Multiple Myeloma Transplant Eligible NDMM TE

3 VCD is preferable to PAD, Mai, Leukemia 215 VTD is superior to VCD, Cavo, Leukemia 215 Len-dex is better than Thal-dex, Gay F Blood 21 ESMO guidelines 217

4 A Randomized Study of Carfilzomib- Lenalidomide-Dexamethasone vs Carfilzomib- Cyclophosphamide-Dexamethasone Induction in Newly Diagnosed Myeloma Patients Eligible for Transplant: High Efficacy in High- and Standardrisk Patients FORTE Gay F, Rota Scalabrini D, Musto P, Belotti A, Galli M, Offidani M, Gambella M, Coha V, Montefusco V, Zamagni E, Zambello R, Ledda A, Grasso M, Aquino S, Esma F, Ribolla R, Tosi P, Pisani F, Annibali O, Liberati A.M, Oliva S, Paris L, Baraldi A, Galieni P, Specchia G, Pescosta N, Palumbo A, Cavo M and Boccadoro M ASH 217 -, #4541

5 MOBILISATION FORTE: KRd vs KCd in newly diagnosed MM 4x 4x NDMM 65 years R 1:1:1 ARM A: KCd* 4x ARM B: KRd High dose therapy ASCT ARM A: KCd* 4x ARM B: KRd 4x ARM C: KRd 8x ARM C: KRd Induction Post-induction response rates and minimal residual disease were evaluated For this analysis, data of the two KRd groups (Arms B and C) were pooled Primary objective: compare efficacy of KRd vs KCd induction in patients eligible for transplantation Secondary objective: evaluate the efficacy of KRd vs KCd in different subgroups according to prognostic features, focusing specifically on high-risk patients *Carfilzomib: 2/36 mg/m 2 IV d 1, 2, 8, 9, 15, 16; cyclophosphamide 3 mg/m 2 d 1, 8, 15; dexamethasone: 2 mg d 1, 2, 8, 9, 15, 16. Carfilzomib and dexamethasone as above; lenalidomide: 25 mg d by multiparameter flow cytometry (8 colours, sensitivity 1-5 ) ASCT, autologous stem cell transplant; KCd, carfilzomib, cyclophosphamide and dexamethasone; KRd, carfilzomib, lenalidomide and dexamethasone; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma.

6 Response (%) Response (%) KRd achieved higher response rates vs KCd in subgroup analyses VGPR rate KRd KCd All patients High risk* Standard risk Stage I Stage II/III Chromosomal abnormalities ISS stage CR rate KRd KCd All patients High risk* Standard risk Stage I Stage II/III Chromosomal abnormalities ISS stage * High risk: del(17p) or t(4;14) or t(14;16). CR, complete response; ISS, International Staging System; KCd, carfilzomib, cyclophosphamide and dexamethasone; KRd, carfilzomib, lenalidomide and dexamethasone;, very good partial response.

7 Autologous SCT remains up-front SoC

8 IFM/DFCI 29 Phase 3 Trial newly diagnosed MM pts 65 years (ASCT candidates) 1 cycle RVD ARM B: Early transplant arm Randomize, stratification ISS & FISH ARM A: Late transplant arm RVD, cycles 2, 3 RVD, cycles 2, 3 CY (3g/m 2 ) + G-CSF MOBILIZATION Goal: cells/kg PBSC collection CY (3g/m 2 ) + G-CSF MOBILIZATION Goal: cells/kg Melphalan 2 mg/m 2 + ASCT Consolidation RVD 5 RVD 2 Lenalidomide 12 mos (IFM) Lenalidomide until relapse (DFCI) Lenalidomide 12 mos (IFM) Lenalidomide until relapse (DFCI) Maintenance ASCT at relapse

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10 European Myeloma Network median PFS NE vs 44mo 3-year estimate of PFS 64% vs 57%, (HR=.76; p=.2) MRD neg (1-5 ) 64% vs 36% Pts with high-risk cytogenetics benefit from double ASCT 3-yr PFS for ASCT-2 vs ASCT-1: 69.2% vs 44.2% (HR:.42; P =.14) Cavo et al, ASH 217

11 Newly Diagnosed Multiple Myeloma Transplant Ineligible NDMM - TI

12 Phase 3 Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE) Mateos MV et al. Oral presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Atlanta, GA, USA; Abstract LBA-4 Mateos MV et al. N Engl J Med 217; Epub ahead of print

13 1:1 Randomization (N = 76) Mateos MV et al. Oral presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Atlanta, GA, USA; Abstract LBA-4 Mateos MV et al. N Engl J Med 217; Epub ahead of print ALCYONE phase 3 study of daratumumab + VMP in NDMM Study Design Key eligibility criteria: Transplantineligible NDMM ECOG -2 Creatinine clearance 4 ml/min No peripheral neuropathy grade 2 Stratification factors ISS (I vs II vs III) Region (EU vs other) Age (<75 vs 75 years) VMP 9 cycles (n = 356) Bortezomib: 1.3 mg/m 2 SC Cycle 1: twice weekly Cycles 2-9: once weekly Melphalan: 9 mg/m 2 PO on Days 1-4 Prednisone: 6 mg/m 2 PO on Days 1-4 D-VMP 9 cycles (n = 35) Daratumumab: 16 mg/kg IV Cycle 1: once weekly Cycles 2-9: every 3 weeks + Same VMP schedule Cycles 1-9: 6-week cycles Cycles 1+: 4-week cycles D Cycles mg/kg IV Every 4 weeks: until PD Followup for PD and survival Primary endpoint: PFS Secondary endpoints: ORR VGPR rate CR rate MRD (NGS; 1 5 ) OS Safety Statistical analyses 36 PFS events: 85% power for 8-month PFS improvement Interim analysis: ~216 PFS events NDMM, newly diagnosed multiple myeloma; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; EU, European Union; VMP, bortezomib/melphalan/prednisone; SC, subcutaneously; PO, orally; D, daratumumab; IV, intravenously; PD, progressive disease; PFS, progression-free survival; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease; NGS, next-generation sequencing; OS, overall survival.

14 % surviving without progression ALCYONE: PFS Pre-specified interim analysis after 231 PFS events Median (range) follow-up: 16.5 ( ) months month PFS a 87% 18-month PFS a 72% 6 76% D-VMP Median: not reached 4 2 5% VMP Median: 18.1 months No. at risk VMP D-VMP HR,.5 (95% CI, ; P <.1) Months a Kaplan-Meier estimate. 5% reduction in the risk of progression or death in patients receiving D-VMP Mateos MV et al. Oral presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Atlanta, GA, USA; Abstract LBA

15 ORR a, % Mateos MV et al. Oral presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Atlanta, GA, USA; Abstract LBA-4 ALCYONE: Response Rates Median duration of response: 21.3 months in VMP versus not reached in D-VMP CR: 24% b ORR = 74% 18 7 CR: 43% P <.1 VGPR: 5% b ORR = 91% VMP (n = 356) D-VMP (n = 35) VGPR: 71% Response Median (range) time to first response, months Median (range) time to best response, months VMP D-VMP (n = 263) c (n = 318) c.82 ( ) 4.11 (.7-2.5).79 ( ) 4.93 (.5-21.) PR VGPR CR scr Significantly higher ORR, VGPR rate, and CR rate with D-VMP; >2-fold increase in rate of scr with D-VMP PR, partial response; scr, stringent complete response. a ITT population. b P <.1; P value was calculated with the use of the Cochran Mantel Haenszel chi-square test. c Responders in responseevaluable population.

16 MRD-negative rate, % % surviving without progression ALCYONE Efficacy: MRD a (NGS; 1 5 Sensitivity Threshold) Median (range) follow-up: 16.5 ( ) months P <.1 3.6X VMP MRD negative D-VMP MRD negative D-VMP MRD positive VMP (n = 356) D-VMP (n = 35) 2 No. at risk VMP MRD negative D-VMP MRD negative VMP MRD positive D-VMP MRD positive Months >3-fold higher MRD-negativity rate with D-VMP; Lower risk of progression or death in all MRD-negative patients VMP MRD positive MRD, minimal residual disease; NGS, next-generation sequencing using clonoseq version 2. (Adaptive); VMP, bortezomib/melphalan/prednisone; D, daratumumab; CR, complete response ; scr stringent complete response. a Assessed at time of confirmation of CR/sCR, and if confirmed, 12, 18, 24, and 3 months after first dose. Mateos MV et al. Oral presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Atlanta, GA, USA; Abstract LBA-4

17 Relapsed/Refractory Multiple Myeloma RRMM

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19 Recommendations for salvage ASCT in RRMM ESMO: In young patients, a second ASCT may be considered, provided that the patient responded well to the previous ASCT and had a PFS of more than 24 months EBMT/ASBMT: High-dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months. NCCN 218: RETROSPECTIVE STUDIES SUGGEST A MINIMUM LENGTH OF 2-3 YEARS OF REMISSION FOR CONSIDERATION OF A SECOND ASCT

20 n=174, G Cook, Leeds 2

21 n=174, G Cook, Leeds 21

22 median PFS 19 mo vs 11 mo (p<.1) 3-year OS 8% vs 63% (ns) G Cook, Leeds NRM 1% vs % 22

23 Multiple retrospective salvage ASCT studies Atanackovic, BJH

24 Multiple retrospective salvage ASCT studies ~3-5% Atanackovic, BJH

25 Multiple retrospective salvage ASCT studies ~15 mo Atanackovic, BJH

26 What to expect from non-transplant relapse treatments? Phase III studies

27 ENDEAVOR Phase III: Carfilzomib and Dexamethasone (Kd) vs Bortezomib and Dexamethasone (Vd) Randomization 1:1 N = 929 Stratification: Prior proteasome inhibitor therapy Prior lines of treatment ISS stage Planned route of bortezomib administration (SQ/IV) Kd Carfilzomib 56 mg/m 2 IV Days 1, 2, 8, 9, 15, 16 (2 mg/m 2 days 1, 2, cycle 1 only) Infusion duration: 3 minutes for all doses Dexamethasone 2 mg Days 1, 2, 8, 9, 15, 16, 22, day cycles until PD or unacceptable toxicity Vd Bortezomib 1.3 mg/m 2 (IV bolus or subcutaneous injection) Days 1, 4, 8, 11 Dexamethasone 2 mg Days 1, 2, 4, 5, 8, 9, 11, day cycles until PD or unacceptable toxicity Primary end point: PFS by IRC Secondary end points: OS ORR DOR Grade 2 PN rate Safety Therapie bis zum Progress ISS, International Staging System; IV, intravenous; PD, progressive disease; SQ, subcutaneous. Dimopoulos M et al. Lancet Oncol. 216;17:27-38

28 ENDEAVOR: Carfilzomib and Dexamethasone (Kd) vs Bortezomib and Dexamethasone (Vd) Key inclusion criteria: Relapsed multiple myeloma 1 3 prior treatments ECOG PS 2 Prior treatment with bortezomib or carfilzomib was allowed if: PR to prior treatment 6 month proteasome inhibitor treatment-free interval Not discontinued due to toxicity LVEF 4% Creatinine clearance 15 ml/min Len refraktäre Patienten durften eingeschlossen werden Key exclusion criteria: Grade 3 or 4 peripheral neuropathy (or grade 2 with pain) within 14 days prior to randomization Myocardial infarction within 4 months prior to randomization New York Heart Association class III or IV heart failure ECOG PS, Eastern Cooperative Oncology Group performance status; LVEF, left ventricular ejection fraction; PR, partial response. Dimopoulos M et al. Lancet Oncol. 216;17:27-38

29 Proportion Surviving Without Progression Primary End Point: Progression-Free Survival Intent-to-Treat Population (N=929) Disease progression or death n (%) Median PFS months HR for Kd vs Vd (95% CI) Kd (n=464) 171 (37) (.44.65) 1-sided P<.1 Vd (n=465) 243 (52) Kd Vd Median follow-up: 11.2 months Months Since Randomization CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; Kd, carfilzomib and dexamethasone; PFS, progression-free survival; Vd, bortezomib and dexamethasone.

30 Proportion surviving without progression Proportion surviving without progression Progression-Free Survival by Prior Lines of Therapy Intent-to-Treat Population (N=929) 1. 1 prior line 2 prior lines Kd Vd Kd Vd Months since randomization Months since randomization Median PFS, months Kd (n = 232) Vd (n = 232) Median PFS, months Kd (n = 232) Vd (n = 233) HR (95% CI).45 (.33.61) HR (95% CI).6 (.47.78) P-value (one sided)* <.1 P-value (one sided)* <.1 *Descriptive; unadjusted for multiplicity. CI, confidence interval For reactive use only. Do not copy or distribute. 215 Amgen Inc. All rights reserved.

31 Proportion surviving without rogression Proportion surviving without progression PFS and ORR by Prior Bortezomib Exposure Intent-to-Treat Population (N = 929) 1. No Prior Bortezomib 1. Prior Bortezomib.8 HR:.48 (95% CI:.35.66) P-value (1-sided): <.1*.8 HR:.56 (95% CI:.44.73) P-value (1-sided): <.1* Kd Vd Kd Vd Months since randomization Months since randomization Kd (n = 214) Vd (n = 213) Kd (n = 25) Vd (n = 252) Median PFS, Median PFS, NE months months ORR, % ORR, % P-value (one P-value (one <.1.51 sided)* sided)* *Descriptive; unadjusted for multiplicity. For reactive use only. Do not copy or distribute. 215 Amgen Inc. All rights reserved.

32 Proportion Surviving 1. Overall survival was significant increased: 21% risk reduction Kd Vd Kd (N = 464) Vd (N = 465) Death, n (%) 189 (4.7) 29 (44.9) Median OS, mo HR (Kd/Vd) 95% CI.791 ( ) p value.1 Number at risk: Kd 464 Vd Months Dimopoulos MA; Lancet Oncol. 217 Aug 23. pii: S (17)

33 Overall Survival according to subgroups: all subgroups benefit from Kd Age (years) < Baseline ECOG PS 1 2 Events (n)/patients (n) Kd Vd 91/223 61/164 37/77 71/221 81/232 13/21 17/23 15/33 21/3 Baseline creatinine clearance (ml/min) < 3 14/28 15/28 3 to < 5 24/57 37/71 5 to < 8 81/186 85/ /193 72/189 ISS stage I 54/25 68/24 II or III 135/ /261 Risk group by FISH* High 55/97 65/113 Standard 16/ /291 Lines of prior treatment 1 79/231 83/ / /236 Prior bortezomib Yes 113/25 124/252 No 76/214 85/213 Previous immunomodulatory drugs Yes 143/326 No 46/138 92/21 85/189 32/66 16/35 49/115 Favours Kd 1 Favours Vd HR (95% CI).85 ( ).71 (.51.98).84 ( ).81 ( ).8 ( ).5 (.26.98).69 ( ).63 ( ).84 ( ).84 ( ).7 (.49 1.).83 ( ).83 ( ).85 ( ).83 ( ).76 (.59.99).84 ( ).75 ( ).86 ( ).66 (.44.99) *Excludes patients with missing or unknown results. High-risk FISH is defined as detection of 1% t(4;14) or t(14;16) genetic subtypes in screened plasma cells, or 2% 17p deletions in screened plasma cells at study entry. Standard-risk patients were those in whom chromosomal abnormalities were not detected. CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group performance status; FISH = fluorescence in situ hybridization; HR = hazard ratio; ISS = International Staging System; Kd = carfilzomib and dexamethasone; Vd = bortezomib and dexamethasone. Dimopoulos et al., Lancet Oncol. 217; e-pub ahead of print

34 ASPIRE - Phase III Study design

35 Primary endpoint: Progression-free survival ITT Population (n=792)

36 Proportion Surviving Without Progression Proportion Surviving Without Progression PFS by Prior Line of Therapy (1 vs 2) 1. 1 prior line of therapy 2 prior lines of therapy KRd Rd Months from Randomization.2 KRd Rd Months from Randomization KRd (n=184) Rd (n=157) KRd (n=212) Rd (n=239) PFS, median months PFS, median months Hazard ratio (95% CI).69 (.52.94) Hazard ratio (95% CI).69 (.54.89) P value (one-sided).8 P value (one-sided).2 CI Confidence interval; KRd, carfilzomib, lenalidomide, and dexamethasone; PFS, progression-free survival; Rd, lenalidomide and dexamethasone.

37 Proportion Surviving KRd Extended Median Overall Survival by 7.9 Months vs Rd 1..8 KRd (n = 396) Rd (n = 396) Death, n (%) 246 (62.1) 267 (67.4) OS, months, median HR (95% CI) for KRd vs Rd.79 (.67.95) 1-sided P = KRd Rd Events at 18 months: KRd, 71 (17.9%); Rd, 97 (24.5%) HR (95% CI) =.69 (.51.93) Number of patients at risk: KRd Rd Months Since Randomization CI = confidence interval; HR = hazard ratio; KRd = carfilzomib, lenalidomide, and dexamethasone; OS = overall survival; Rd = lenalidomide and dexamethasone. Siegel DS, et al; [published online ahead of print January 17, 218]. J Clin Oncol. doi: 1.12/JCO Stewart AK, et al. Slides presented at: Annual Meeting of the American Society of Hematology; December 9-12, 217; Atlanta, GA. 37

38 Carfilzomib is currently the only myeloma drug that has demonstrated significant OS benefit in 2 phase III trials in relapsed/ refractory setting compared to SoC Aspire * KRd27: 48.3 Monate Rd: 4.4 Monate HR =.79 [95% CI,.67.95] Endeavor ** Kd56: 47.6 Monate Vd: 4. Monate HR =.791 [95% CI ] Monate *Kyprolis was given as defined in study protocol for a maximum of 18 cycles, Rd was continued until progression in both arms ** In der post hoc Analyse nach 3 Jahren (FDA gefordertes Marketing Requirement) konnte eine Reduktion des Mortalitätsrisikos um 24% und eine Verlängerung des Gesamtüberlebens um 9 Monate im Vergleich zum Vd Arm gezeigt werden. (OS 47,8 Monate für Kd versus 38,8 Monate für Vd, HR=,76; 95 % CI,,63-,92; p=,17) Press releases: THOUSAND OAKS, Calif. (July 12, 217); THOUSAND OAKS, Calif. (Aug. 3, 217); Lancet Oncol. 217 Aug 23. pii: S (17) doi: 1.116/S (17) Do not copy or distribute. 217 Amgen. All rights reserved

39 Daratumumab, Bortezomib, and Dexamethasone (DVd) Versus Bortezomib and Dexamethasone (Vd) in Relapsed or Refractory Multiple Myeloma (RRMM): Updated Efficacy and Safety Analysis of CASTOR Spencer A et al. Poster presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 3145

40 CASTOR phase 3 study of DVd vs Vd in RRMM Study Design Clinical cutoff date: 3 August 217 Median duration of follow-up: 26.9 months Median duration of treatment: DVd, 13.4 months; Vd, 5.2 months Premedication for the DVd treatment group consisted of dexamethasone 2 mg, acetaminophen, and an antihistamine DVd, daratumumab, bortezomib and dexamethasone; IV, intravenous; V, bortezomib; SC, subcutaneously; d, dexamethasone; PO, orally; VD, bortezomib and dexamethasone; D, daratumumab; Obs, observation; PFS, progressionfree survival; TTP, time to progression; OS, overall survival; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease; ISS, International Staging System. Spencer A et al. Poster presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 3145

41 CASTOR updated analysis PFS: ITT and Prior Lines of Therapy PFS (A) in the ITT population and (B) based on prior lines of therapy Median duration of follow-up: 26.9 months Addition of daratumumab to Vd continues to significantly prolong PFS with longer follow-up. Patients who received 1 prior line of therapy benefitted the most from DVd Spencer A et al. Poster presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 3145

42 CASTOR updated analysis: PFS by prior lines of therapy PFS based on prior lines of therapy Median duration of follow-up: 26.9 months DVd improved PFS regardless of the number of prior lines of therapy Spencer A et al. Poster presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 3145

43 Daratumumab, Lenalidomide, and Dexamethasone (DRd) Versus Lenalidomide and Dexamethasone (Rd) in Relapsed or Refractory Multiple Myeloma (RRMM): Updated Efficacy and Safety Analysis of POLLUX Dimopoulos MA et al. Oral presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 739

44 POLLUX Study Design DRd (n = 286) Key eligibility criteria RRMM 1 prior line of therapy Prior lenalidomide exposure allowed, but not if lenalidomide refractory Creatinine clearance 3 ml/min R A N D O M I Z E 1:1 Daratumumab 16 mg/kg IV Every week in Cycles 1-2 Every 2 weeks in Cycles 3-6 Every 4 weeks Lenalidomide 25 mg PO Days 1-21 of each cycle Dexamethasone 4 mg PO a Every week Treatment until PD Rd (n = 283) Primary endpoint PFS Secondary endpoints OS ORR, VGPR, CR MRD Time to response Duration of response Stratification factors No. of prior lines of therapy ISS stage at study entry Lenalidomide 25 mg PO Days 1-21 of each cycle Dexamethasone 4 mg PO Every week Treatment until PD Statistical analyses Final OS analysis at 33 OS events Prior lenalidomide Cycles: 28 days

45 % surviving without progression POLLUX updated analysis: PFS Progression-free survival a month PFS b No. at risk Rd DRd Months % 35% HR.44; 95% CI, ; P <.1 Median follow-up: 32.9 months (range, - 4. months) DRd Median: not reached Rd Median: 17.5 months 56% reduction in risk of progression/death for DRd versus Rd Dimopoulos MA et al. Oral presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 739

46 MRD-negative rate, % POLLUX updated analysis: ORR and MRD-negative rates a Median follow-up: 32.9 months (range, - 4. months) Overall Response Rate a MRD-negative Rate *P <.1 * * * ,4 DRd Rd DRd Rd DRd Rd MRD assessed using clonoseq assay V2. Responses continued to deepen in the DRd group Significantly higher (>3-fold) MRD-negative rates for DRd versus Rd scr, stringent complete response; PR, partial response. Primary analysis reported in Dimopoulos MA, et al. N Engl J Med. 216;375(14): a Exploratory analyses based on clinical cutoff date of October 23, 217; b P <.1 for DRd versus Rd. Dimopoulos MA et al. Oral presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 739

47 MRD-negative patients, % % surviving without progression POLLUX: Time to MRD Negativity and PFS by MRD Status 4 Time to MRD Negativity (1-5 ) PFS by MRD Status (1-5 ) DRd DRd MRD Rd MRD DRd MRD+ 1 Rd 2 Rd MRD+ No. at risk Rd DRd Months No. at risk Rd MRD negative DRd MRD negative Rd MRD positive DRd MRD positve Months MRD negativity occurs more rapidly with DRd and increases over time Achievement of MRD negativity was associated with prolonged PFS Dimopoulos MA et al. Oral presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 739

48 POLLUX updated analysis: Subgroup analyses Progression-free survival Prior lenalidomide exposure Cytogenetic status Refractory to bortezomib Median follow-up: 32.9 months DRd improved PFS, ORR, scr and MRD ve rates versus Rd regardless of prior treatment, cytogenetic risk or moderate renal impairment Moreau P et al. Poster presentation at: 59th American Society of Hematology Moreau (ASH) P, Annual et al. Presented Meeting and at Exposition; ASH 217 December (Abstract ), 217; poster Abstract presentation 1883

49 Treatment for relapse post / prior AutoSCT - PFS expectations Doublet (Rd, Vd) : ~12-18 months K-doublet or triplet (Kd, KRd) : ~ >24 months Dara-triplet (DRd) : ~2-3 years AE/treatment-related deaths ~5% (<1%) Versus salvage ASCT : months

50 Conclusions: 2nd/salvage AutoSCT for relapse safe (NRM<5%, minimal SPM effect) straight-forward (outpatient basis, cells stored) effective (PFS > 2years with modern re-induction and maintenance?) Open Questions: Superior to non-sct approaches (triple therapies)? Maintenance? Conditioning? PFS1 (18mo 36mo) or response-to-reinduction cut-off? Molecular risk?

51 Proposed algorithm for the treatment of initial, intermediate or advanced myeloma relapses Red: most potent // blue: less expensive Chim Leukemia 217

52 VIELEN DANK FÜR DIE AUFMERKSAMKEIT

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54 CANDOR: A Randomized, Open-label, Phase 3 Study comparing Carfilzomib, Dexamethasone and Daratumumab to Carfilzomib and Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma EudraCT number Currently enrolling. 54 Do not copy or distribute. 217 Amgen. All rights reserved

55 Mateos MV et al. Oral presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Atlanta, GA, USA; Abstract LBA-4 ALCYONE: Baseline Demographics and Disease Characteristics Age VMP (N = 356) D-VMP (N = 35) Median (range), years 71. (5-91) 71. (4-93) Distribution, n (%) <65 years 24 (7) 36 (1) years 225 (63) 21 (6) 75 years 17 (3) 14 (3) Male, n (%) 167 (47) 16 (46) Race, n (%) White 34 (85) 297 (85) Others 52 (15) 53 (15) ECOG status a, n (%) Baseline Characteristics 99 (28) 78 (22) (49) 182 (52) 2 84 (24) 9 (26) Type of multiple myeloma b, n (%) VMP (N = 356) D-VMP (N = 35) IgG 229 (64) 224 (64) IgA 82 (23) 73 (21) ISS stage c, n (%) I 67 (19) 69 (2) II 16 (45) 139 (4) III 129 (36) 142 (41) Median (range) time from multiple myeloma diagnosis, months Cytogenetic profile d, n (%) Disease Characteristics.82 ( ).76 ( ) N = 32 N = 314 Standard risk 257 (85) 261 (83) High risk 45 (15) 53 (17) a ECOG performance status is scored on a scale from to 5, with indicating no symptoms and higher scores indicating increasing disability. b Determined by immunofixation or serum free light chain assay. c Based on the combination of serum β2-microglobulin and albumin. d Based on fluorescence in situ hybridization/karyotype testing performed at local sites.

56 Mateos MV et al. Oral presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Atlanta, GA, USA; Abstract LBA-4 ALCYONE Safety: Most Common TEAEs a VMP (n = 354) D-VMP (n = 346) Any Grade Grade 3 or 4 Any Grade Grade 3 or 4 Hematologic, n (%) Neutropenia 186 (53) 137 (39) 172 (5) 138 (4) Thrombocytopenia 19 (54) 133 (38) 169 (49) 119 (34) Anemia 133 (38) 7 (2) 97 (28) 55 (16) Nonhematologic, n (%) Peripheral sensory neuropathy 121 (34) 14 (4) 98 (28) 5 (1) Upper respiratory tract infection 49 (14) 5 (1) 91 (26) 7 (2) Diarrhea 87 (25) 11 (3) 82 (24) 9 (3) Pyrexia 74 (21) 2 (1) 8 (23) 2 (1) Nausea 76 (22) 4 (1) 72 (21) 3 (1) Pneumonia 17 (5) 14 (4) 53 (15) 39 (11) 1 patient in each arm discontinued treatment due to pneumonia 1.4% and.9% of patients receiving VMP and D-VMP, respectively, discontinued treatment due to infection VMP (n = 354) D-VMP (n = 346) Deaths due to TEAEs, n (%) 19 (5) 19 (6) TEAE, treatment-emergent adverse event; VMP, bortezomib/melphalan/prednisone; D, daratumumab. a Any grade TEAEs in 2% of patients and grade 3 or 4 TEAEs in 1% of patients in either treatment group.

57 Subsequent anti-myeloma therapies were balanced Kd (n = 391) Vd (n = 413) Number of patients treated with at least one therapy 262 (67%) 291 (7%) Systemic corticosteroids Dexamethasone 189 (48%) 22 (53%) Prednisone 2 (5%) 32 (8%) Prednisolone 19 (5%) 15 (4%) Proteasome inhibitors Bortezomib 98 (25%) 51 (12%) Carfilzomib 3 (1%) 33 (8%) Immunomodulatory drugs Lenalidomide 125 (32%) 152 (37%) Pomalidomide 64 (16%) 99 (24%) Thalidomide 36 (9%) 55 (13%) Monoclonal antibodies Daratumumab 14 (4%) 18 (4%) Data are n (%) of patients for therapies for which 2% or more of patients were given subsequent therapies. On completion of Kd or Vd therapy, 391 patients in the Kd group (of 397 completing therapy) and 413 patients in the Vd group (of 418 completing therapy) entered long-term follow-up. Dimopoulos et al., Lancet Oncol. 217; e-pub ahead of print

58 Subsequent anti-myeloma therapies were well balanced Antineoplastic agents Kd (n = 391) Vd (n = 413) Cyclophosphamide 85 (22%) 12 (25%) Melphalan 5 (13%) 53 (13%) Bendamustine 2 (5%) 35 (8%) Doxorubicin 25 (6%) 21 (5%) Etoposide 14 (4%) 15 (4%) Cisplatin 12 (3%) 15 (4%) Vincristine 11 (3%) 7 (2%) Other therapeutic products Investigational drug 7 (2%) 11 (3%) Data are n (%) of patients for therapies for which 2% or more of patients were given subsequent therapies. On completion of Kd or Vd therapy, 391 patients in the Kd group (of 397 completing therapy) and 413 patients in the Vd group (of 418 completing therapy) entered long-term follow-up. Note: Data on response were not collected for subsequent treatment and thus are not available Dimopoulos et al., Lancet Oncol. 217; e-pub ahead of print

59 Post-hoc Landmark-Analysis : OS from time of progression is identical OS from time of progression is 21.5 months in both arms Both curves are identical thus indicating that the PFS benefit gained under Kd treatment is responsible for the OS benefit in the Kd arm. Dimopoulos MA; Lancet Oncol. 217 Aug 23. pii: S (17)

60 Aspire Conclusions KRd demonstrated a statistically significant and clinically meaningful reduction in the risk of death vs Rd, improving the median OS by 7.9 months (48.3 vs 4.4 months; HR =.79; P =.45) Median OS at first relapse improved by 11.4 months with KRd (47.3 vs 35.9 months; HR =.81) HR = hazard ratio; KRd = carfilzomib, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone; OS = overall survival. Treatment with KRd did not compromise Siegel DS, et al; [published online ahead of print January 17, 218]. J Clin Oncol. doi: 1.12/JCO overall survival after relapse

61 CASTOR: Overview of safety profile All grades 25% Grades 3/4 5% TEAE DVd Vd DVd Vd Hematologic (%) Thrombocytopenia Anemia Neutropenia Lymphopenia Nonhematologic (%) Pneumonia Peripheral sensory neuropathy Hypertension Upper respiratory tract infection Diarrhea Cough The safety profile was consistent with previous analyses of CASTOR TEAE-related treatment discontinuations occurred in 9.5% and 9.3% of patients in the DVd and Vd arms, respectively With longer follow-up, secondary primary malignancies were reported in 1 (4.1%) and 3 (1.3%) patients who received DVd and Vd, respectively The safety profile of DVd remains consistent with previous studies and no new safety signals were reported Spencer A et al. Poster presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 3145

62 CASTOR updated analysis: OS Per study protocol, long-term survival follow-up will continue until 32 deaths have been observed in both arms (i.e, when two-thirds of the randomized patients have died) OS data currently remain immature Lentzsch S et al. Poster presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 1852

63 CASTOR: Efficacy Summary Table Primary Analysis 1 ASH ASCO ASH DVd Vd DVd Vd DVd Vd DVd Vd Median follow-up (range) Median PFS a, mo NE 7.2 NE HR (95% CI) P value.39 ( ) P <.1.33 ( ) P <.1.31 ( ) P <.1.32 (.25-.4) P <.1 ORR b, % CR, % MRD-negative (1-5 ) a, % N/A N/A a ITT population. b Response evaluable population. 1 Palumbo A, et al. N Engl J Med. 216;375(8): Mateos MV, et al. Oral presentation at ASH 216. Abstract: Lentzsch S, et al. Poster presentation at ASCO 217. Abstract: Spencer A, et al. Poster presentation at ASH 217. Abstract: 3145.

64 CASTOR updated analysis ORR and MRD-negative rate (1-5 ) ORR a ITT Population 1 prior LOT 2 prior LOT 3 prior LOT 1-3 prior LOT DVd Vd DVd Vd DVd Vd DVd Vd DVd Rd N % P value < <.1 VGPR, % P value <.1 <.1 < <.1 CR, % P value <.1 < <.1 scr, % MRD-negative rate (1-5 ) b N % P value < <.1 DVd improved ORR regardless of the number of prior lines of therapy Higher MRD-negative rates were observed with DVd a Response-evaluable population. b ITT population. Spencer A et al. Poster presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 3145

65 CASTOR updated analysis: PFS by response and MRD status PFS in patients who achieved (A) CR and (B) MRD negativity at 1-5 (clonoseq V2.) PFS among patients who achieved deep responses was prolonged with DVd versus Vd. MRD negativity was associated with prolonged PFS Spencer A et al. Poster presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 3145

66 CASTOR updated analysis: PFS2 PFS2 in (A) the ITT Population and in (B) Patients Who Received 1 Prior Line of Therapy A. B. PFS2 is defined as the time from randomization to PD after the next line of subsequent therapy or death Addition of daratumumab to Vd leads to persistent benefit after next line of therapy Lentzsch S et al. Poster presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 1852

67 POLLUX: Overview of Safety profile TEAE, % Hematologic Neutropenia Febrile neutropenia Anemia Thrombocytopenia Lymphopenia Nonhematologic Diarrhea Upper respiratory tract infection Viral upper respiratory tract infection Fatigue Cough Constipation Muscle spasms Nausea Pneumonia Hypokalemia DRd (n = 283) All grades Grade 3/4 ( 25%) a ( 5%) a Rd (n = 281) DRd (n = 283) Rd (n = 281) Median duration of treatment: 3.4 months for DRd versus 16. months for Rd Discontinuations due to TEAEs were similar (13% in both arms) Rate of grade 3/4 infections: 39% for DRd versus 26% for Rd No differences in rates of SPMs between treatment groups (7% of patients in both groups) Most common SPM in both arms was cutaneous, non-invasive SCC (2% each) Safety profile remains unchanged with longer follow-up TEAE, treatment-emergent adverse event; SPM, secondary primary malignancy; SCC, squamous cell carcinoma. a Common TEAEs listed are either 25% all grade OR 5% grade 3/4. Dimopoulos MA et al. Oral presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 739

68 POLLUX: Efficacy Summary Table Primary Analysis 1 ASH ASCO ASH DRd Rd DRd Rd DRd Rd DRd Rd Median follow-up (range) Median PFS a, mo NE 18.4 NE 17.5 NE 17.5 NE 17.5 HR (95% CI) P value.37 ( ) P <.1.37 (.28-.5) P <.1.41 ( ) P <.1.44 ( ) P <.1 ORR b, % CR b, % MRD-negative (1-5 ) a, % OS data are immature; long term follow-up will continue until 33 events are observed a ITT population. b Response evaluable population. 1 Dimopoulos MA, et al. N Engl J Med. 216;375(14): Usmani SZ, et al. Oral presentation at ASH 216. Abstract: Bahlis NJ, et al. Poster presentation at ASCO 217. Abstract: Dimopoulos MA, et al. Oral presentation at ASH 217. Abstract: 739.

69 % surviving without progression POLLUX: PFS with Subsequent Line of Therapy (PFS2) 1 3-month PFS2 a 8 73% 6 58% DRd No. at risk Rd DRd Months HR.51; 95% CI, ; P < DRd does not negatively impact outcomes of subsequent therapy Rd Median: 32.3 months Dimopoulos MA et al. Oral presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 739

70 % surviving without progression % surviving without progression POLLUX: PFS by Depth of Response 1 Response Category MRD Status (1 5 ) DRd CR Rd CR DRd VGPR Rd VGPR DRd MRD Rd MRD DRd MRD+ 2 2 Rd MRD+ No. at risk DRd CR Rd CR DRd VGPR Rd VGPR Months No. at risk Rd MRD negative DRd MRD negative Rd MRD positive DRd MRD positve Months Deeper responses were more common on DRd and were associated with longer PFS MRD negativity was associated with longer PFS Dimopoulos MA et al. Oral presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 739

71 CASTOR updated analysis PFS2 Based on Cytogenetic Risk and MRD-negativity PFS2 in (A) patients with high cytogenetic risk and (B) patients achieving MRD-negativity at 1-5 A. B. Lentzsch S et al. Poster presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December ; Abstract 1852

72 Patients (%) KRd induction had an acceptable safety profile Safety profile of KRd vs KCd induction Grade 3-4 haematologic AEs* Grade 3-4 nonhaematologic AEs* Grade 3-4 CV AEs Treatment discontinuation due to AE KRd KCd The most frequent grade 3-4 haematologic AE was neutropenia (KRd 6% vs KCd 5%) The most frequent grade 3-4 non-haematologic AEs were manageable cutaneous toxicity (KRd 8% vs KCd 1%, p<.1) and reversible increase in liver enzymes (KRd 8% vs KCd 1%, p<.1) Treatment discontinuation due toaes was reported in 4% of KRd and 2% of KCd patients *Rate of 1 AE. AE, adverse events; CV, cardiovascular; KCd, carfilzomib, cyclophosphamide and dexamethasone; KRd, carfilzomib, lenalidomide and dexamethasone.